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Metabolic signature of methylone in primary mouse hepatocytes, at subtoxic concentrations

2019Journal article Restricted access
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dc.contributor.authorAraújo, Ana Margarida
dc.contributor.authorCarvalho, Márcia
dc.contributor.authorBastos, Maria de Lourdes
dc.contributor.authorCarvalho, Félix
dc.contributor.authorGuedes de Pinho, Paula
dc.date.accessioned2021-06-30T10:54:22Z
dc.date.available2021-06-30T10:54:22Z
dc.date.issued2019
dc.description.abstractMethylone (3,4-methylenedioxymethcathinone) is one of the most popular new psychoactive drugs worldwide. Although advertised as a safe drug, its use has been associated to several cases of liver damage. In this work, a metabolomics approach based on gas chromatography-mass spectrometry (GC-MS) combined with chemometric analyses was used to characterize the disturbances occurring in the intra- and extracellular metabolome of primary mouse hepatocytes exposed to two subtoxic concentrations (LC01 and LC10) of methylone to better understand the early hepatotoxic events. Results showed a characteristic metabolic fingerprint for methylone, where aspartate, cysteine, 2-methyl-1-pentanol, 4-methylheptane, dodecane, 2,4-dimethyl-1-heptene, 1,3-di-tert-butylbenzene, acetophenone, formaldehyde and glyoxal levels were significantly changed at both concentrations tested. Furthermore, subtoxic concentrations of methylone caused profound changes in several biochemical pathways, suggesting adaptations in energy production processes (TCA cycle, amino acids metabolism and pyruvate metabolism), cellular antioxidant defenses (glutamate, cysteine and glutathione metabolism) and hepatic enzymes (associated to hydrocarbons, alcohols, aldehydes and ketones metabolism). This metabolic response to the initial methylone challenge most probably reflects the activation of protective mechanisms to restore cellular homeostasis. Overall, this study highlights the potential of untargeted metabolomic analysis to reveal the hepatic metabolic signature of methylone at subtoxic concentrations, and also provides clues to clarify the early mechanisms underlying the toxicity triggered by this new psychoactive substance, opening a new perspective for the study of toxicity mechanisms of new xenobiotics.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.doi10.1007/s00204-019-02566-8pt_PT
dc.identifier.eissn1432-0738
dc.identifier.issn0340-5761
dc.identifier.urihttp://hdl.handle.net/10284/9978
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringerpt_PT
dc.relationThis work received financial support from the European Union (FEDER funds POCI/01/0145/FEDER/007728) and National Funds (FCT/MEC, Fundação para a Ciência e a Tecnologia and Ministério da Educação e Ciência) under the Partnership Agreement PT2020 UID/MULTI/04378/2013. The study is a result of the project NORTE-01-0145-FEDER-000024, supported by Norte Portugal Regional Operational Program (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement (DESignBIOtecHealth—New Technologies for three Health Challenges of Modern Societies: Diabetes, Drug Abuse and Kidney Diseases), through the European Regional Development Fund (ERDF). A. M. Araújo thanks to FCT for her PhD fellowship (SFRH/BD/107708/2015) and M. Carvalho also acknowledges FCT through the UID/MULTI/04546/2019 project.pt_PT
dc.subjectPrimary mouse hepatocytespt_PT
dc.subjectMethylonept_PT
dc.subjectMetabolomicspt_PT
dc.subjectGC–MSpt_PT
dc.subjectHepatotoxicitypt_PT
dc.subjectIntracellular and extracellular metabolite profilingpt_PT
dc.titleMetabolic signature of methylone in primary mouse hepatocytes, at subtoxic concentrationspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage3290pt_PT
oaire.citation.startPage3277pt_PT
oaire.citation.titleArchives of Toxicologypt_PT
oaire.citation.volume93pt_PT
person.familyNameCarvalho
person.givenNameMarcia
person.identifier2017111
person.identifier.ciencia-id8B10-171E-E63E
person.identifier.orcid0000-0001-9884-4751
person.identifier.ridD-5999-2013
person.identifier.scopus-author-id7201413997
rcaap.rightsclosedAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication3837b828-ba57-47f7-a811-cce65e4922c6
relation.isAuthorOfPublication.latestForDiscovery3837b828-ba57-47f7-a811-cce65e4922c6

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